Nuances in sequencing systemic and local therapy for mHSPC

During a recent Urology Times Clinical Forum in Tampa, Florida, a group of urologists gathered to discuss current treatment paradigms for metastatic hormone-sensitive prostate cancer. Among the topics addressed were advanced imaging modalities as well as the comparative efficacy and tolerability of androgen receptor pathway inhibitors. Alexander Engelman, MD, of Florida Urology Partners in Tampa, served as moderator for the Clinical Forum.

This summary was generated by artificial intelligence and edited by humans for clarity.

A significant portion of the discussion examined the utility and limitations of advanced imaging modalities, such as prostate-specific membrane antigen (PSMA)-PET scans, in staging and disease assessment. One case involved a 62-year-old man presenting with fatigue, low back pain, an elevated prostate-specific antigen (PSA) level of 57 ng/mL, and biopsy results indicating Gleason 9 disease. Initial conventional imaging with CT and bone scans revealed multiple bone metastases but no visceral lesions. Participants debated the potential added value of PSMA-PET imaging in this context. Although some experts noted that PSMA-PET could detect additional small metastatic lesions and might influence management decisions—possibly shifting a patient from a high-volume to a lower-volume disease classification—others emphasized that the additional sensitivity might not significantly alter treatment choices, especially if the standard CT and bone scan provide sufficient staging information. The consensus leaned toward a nuanced application of PSMA-PET, recognizing its higher sensitivity but also acknowledging that findings might not always lead to different treatment pathways, particularly in cases with a clear metastatic burden identified on conventional scans.

Further, the discussion considered the implications of incorporating advanced imaging into clinical decision-making, especially related to treatment intensification strategies and the timing of systemic therapy vs localized interventions such as radiation. When evaluating patients with limited metastatic disease, experts deliberated on the sequencing of systemic therapy, radiation, and the role of PSMA-PET in potentially detecting occult metastases that could alter the treatment approach. The case of a patient with 7 metastatic lesions—bone, rib cage, pelvis, lymph node, and a tiny liver lesion—was discussed, illustrating that treatment plans often involve systemic therapy with agents like androgen deprivation therapy (ADT) combined with novel hormonal agents, before contemplating localized radiation. The experts underscored the importance of systemic therapy in controlling disease burden and highlighted that PSMA-PET findings—such as additional small lesions—might influence decisions to escalate systemic therapy or to incorporate targeted radiation.

Transitioning from imaging to systemic therapy, the panel discussed the comparative efficacy of drugs such as abiraterone acetate (Zytiga), enzalutamide (Xtandi), apalutamide (Erleada), and darolutamide (Nubeqa). The expertise shared suggested a trend toward using increasingly effective androgen receptor pathway inhibitors, especially in high-risk or high-volume disease. Data from real-world references and retrospective analyses were mentioned, indicating a tendency among clinicians to prefer certain agents based on tolerability, adverse event (AE) profiles, and insurance coverage. Darolutamide, specifically, was referenced in relation to its safety profile and role in delaying disease progression. Although detailed comparative efficacy data between these agents are limited, the panel indicated that darolutamide is gaining favor particularly because of its lower central nervous system penetration, which might translate into fewer cognitive AEs compared with enzalutamide. The panelists acknowledged that selecting among these agents involves weighing factors such as AE profile, patient comorbidities (including cardiovascular and cognitive considerations), and logistics like pill burden and cost coverage. There was a consensus that soon, combinations like darolutamide plus androgen deprivation are becoming standard options for certain patient populations, aligning with emerging trends toward more aggressive or upfront combination therapies.

The conversation also touched upon the optimal duration of systemic therapy and the importance of PSA response as a marker of treatment efficacy. Experts discussed the goal of achieving extremely low PSA levels, such as undetectable or very low PSA, considering whether this should be a benchmark for therapeutic success in castrate-sensitive disease. The potential benefit of extending ADT duration beyond traditional timelines to longer courses was examined, particularly in high-grade disease. The management of elderly patients or those with significant comorbidities was also addressed, with some clinicians advocating for more conservative approaches, especially when considering the tolerability of chemotherapy or aggressive systemic therapy.

Another theme in the discussion was the integration of newer agents and treatment intensification strategies into routine practice. There was acknowledgment of the underuse of combination therapies, partly driven by concerns about toxicity, AEs, and access issues such as drug coverage costs. Several speakers emphasized that cost remains a substantial barrier, especially given the high monthly expenses associated with novel hormonal agents. Even with insurance coverage, co-pays and the availability of assistance through foundations influence patient access. Clinicians also debate the value of systemic treatment escalation, mentioning that about half of all patients with metastatic disease do not receive dual therapy, despite evidence suggesting that combination approaches improve long-term outcomes. The panelists advocate for broader adoption while recognizing that systemic factors, including economic barriers, need addressing to optimize therapy delivery.

Regarding the choice of specific agents, such as darolutamide, enzalutamide, or apalutamide, clinicians considered various factors, including AE profiles, ease of use, pill burden, and insurance approval processes. Darolutamide was viewed favorably by some due to its minimal central nervous system penetration, which may result in fewer cognitive AEs—particularly relevant in older patients or those with pre-existing cognitive concerns. The ease of medication coverage is also discussed, noting that certain drugs such as enzalutamide or apalutamide may be easier to prescribe depending on insurer networks. Experts mentioned that treatment decision-making is often tailored to individual patient characteristics, including prior medical history, comorbidities, and preferences, with clinicians leaning toward darolutamide when AE minimization is a priority.

Throughout the discussion, several patient cases exemplified the nuanced approach clinicians take, balancing disease burden, patient age, comorbidities, and treatment tolerability. For example, an 84-year-old man with Gleason 9 disease and widespread positive cores was considered for treatment strategies that weigh the risks and benefits of systemic therapy vs radiation or observation. Some clinicians advocate for administering short courses of ADT or even forgoing systemic therapy if the patient's overall health status suggests that aggressive treatment may not substantially improve quality of life or prognosis. Conversely, in younger, fitter patients with high-volume disease, the consensus favored early, comprehensive systemic treatment, often combining ADT with novel hormonal agents.

The panel also discussed ongoing trials and emerging evidence that are likely to refine future practice—particularly the role of metastasis-directed therapy like radioimmunotherapy or the use of novel agents. Although some clinicians stated that such approaches are under study and not yet standard, they reflect a trend toward more individualized, selective treatment based on disease distribution, imaging results, and patient preferences.

In summary, this Clinical Forum encapsulated a clinician-driven dialogue about optimizing management strategies for metastatic prostate cancer, especially in the hormone-sensitive setting. It highlighted the importance of sophisticated imaging, the evolving landscape of systemic therapies—including darolutamide—and the ongoing challenge of integrating new evidence into clinical practice amid barriers such as cost and AE considerations. The discussion underscored that therapeutic decisions remain nuanced and personalized, aiming to balance disease control with quality of life, all within the constraints of evolving evidence and health care systems.